Study of plant coumarins 1. Transformations of peucedanin

Article abstract of DOI:10.1007/s11172-006-0263-6

The structure of 2-bromooreoselon, which was prepared by bromination of peucedanin or oreoselon with molecular bromine, was established. The compositions and structures of the reaction products of this bromide with amines, such as pyridine, triethylamine, and morpholine, as well as with sodium acetate and potassium hydroxide were studied. The reaction of peucedanin with m-chloroperoxybenzoic acid affords peuruthenicin isobutyrate.

Full text of DOI:10.1007/s11172-006-0263-6

Russian Chemical Bulletin, International Edition, Vol. 55, No. 2, pp. 375—379, February, 2006
375
Study of plant coumarins
1
. Transformations of peucedanin
S. A. Osadchii, E. E. Shul´ts,ꢀ M. M. Shakirov, and G. A. Tolstikov
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9
prosp. Akad. Lavrent´eva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. Eꢀmail: schultz@nioch.nsc.ru
The structure of 2ꢀbromooreoselon, which was prepared by bromination of peucedanin or
oreoselon with molecular bromine, was established. The compositions and structures of the
reaction products of this bromide with amines, such as pyridine, triethylamine, and morpholine,
as well as with sodium acetate and potassium hydroxide were studied. The reaction of peucedanin
with mꢀchloroperoxybenzoic acid affords peuruthenicin isobutyrate.
Key words: coumarins, furocoumarins, peucedanin, oreoselon, peuruthenicin, mꢀchloroꢀ
peroxybenzoic acid, bromination, quaternization.
Coumarins produced by higher plants and fungi and
those prepared by synthetic methods can serve as biologiꢀ
cally active compounds of medical interest and, conꢀ
mented. We established the structure of the monobromide
by comparing the H NMR spectra of this compound and
1
oreoselon. The fact that the spinꢀspin coupling of the
signal for the H atom bound to the tertiary C atom of the
isopropyl group in the bromide is simpler (septet, J =
6.8 Hz) compared to the signal for the corresponding
H atom in oreoselon (septet of doublets, J = 6.8 Hz, J =
4.0 Hz) indicates that the H(2) atom in the latter comꢀ
pound is replaced by Br. Therefore, the monobromide
under study is 2ꢀbromooreoselon (2ꢀbromoꢀ2ꢀ(1ꢀmethylꢀ
ethyl)ꢀ7Hꢀfuro[3,2ꢀg][1]benzopyranꢀ3,7ꢀdione (3)). It
was demonstrated that the yields of bromide 3 prepared
by bromination of peucedanin and oreoselon with an
equimolar amount of molecular bromine were 92 and
98%, respectively.
1
—3
cequently, have attracted considerable attention.
Furocoumarinꢀcontaining drugs, which exert the photoꢀ
sensitizing and photoprotective action, such as psoralen,
isopsoralen, 8ꢀmethoxypsoralen, bergapten, and isoꢀ
4
pimpinellin, are used in therapy of skin diseases. 4ꢀHydrꢀ
4
oxycoumarin derivatives are used as anticoagulants. Some
plant coumarins hold considerable promise as antiviral
5
—8
9—12
(
antiꢀHIV)
and antitumor agents.
Siberian flora is endowed with plants valuable as
sources of coumarins.1 Among these plants is, undoubtꢀ
edly, Peucedanum (Peucedanum morisonii Bess., the
Apiaceae or Umbelliferae family), which is widespread
in Western Siberia.1 Thirteen coumarin derivatives
3
4
We studied the behavior of bromide 3 in reactions with
amines. Refluxing of 3 with pyridine in 95% ethanol afꢀ
forded a quaternization product, viz., Nꢀ{2ꢀ(1ꢀmethylꢀ
ethyl)ꢀ3,7ꢀdioxoꢀ7Hꢀfuro[3,2ꢀg][1]benzopyranꢀ2ꢀyl}pyriꢀ
dinium bromide (4), which was isolated as monohydrate.
The reaction was accompanied by the formation
of the already known 2ꢀ(1ꢀmethylethylidene)ꢀ7Hꢀ
1
5
were identified in roots of this plant. Furocoumarin
peucedanin (1) can easily be isolated in a yield of 4% of
the weight of the dry material. It is known that peucedanin
1
6
sensitizes photohemolysis and exhibits antitumor activꢀ
1
7
ity. The pronounced biological activity and availability
of peucedanin have stimulated our interest in studying its
chemical properties.
1
9
furo[3,2ꢀg][1]benzopyranꢀ3,7ꢀdione (5) as a result
of elimination of HBr from the starting bromide 3. In
addition, we isolated 2ꢀethoxyoreoselon (2ꢀethoxyꢀ2ꢀ
The aim of the present study was to synthesize
peucedanin derivatives by modifications of the furan ring.
(
1ꢀmethylethyl)ꢀ7Hꢀfuro[3,2ꢀg][1]benzopyranꢀ3,7ꢀ
dione (6)). Compounds 4, 5, and 6 were obtained in 67,
2, and 7% yields, respectively. Refluxing in chloroform
Results and Discussion
2
Bromination of peucedanin (1) with an equimolar
amount of bromine has been reported1 to afford monoꢀ
bromide identical to that prepared by bromination of
oreoselon (2) (the hydrolysis product of peucedanin) unꢀ
der the same conditions (Scheme 1). However, the yields
and the structure of this monobromide have not docuꢀ
under analogous conditions afforded compounds 4 and 5
in 62 and 17% yields, respectively. Under analogous conꢀ
ditions, refluxing of bromide 3 with more basic triethylꢀ
amine in chloroform gave compound 5 in 47% yield.
Storage of bromide 3 with morpholine in chloroform at
25 °C for 24 h led to the nucleophilic substitution of
8
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 362—366, February, 2006.
066ꢀ5285/06/5502ꢀ0375 © 2006 Springer Science+Business Media, Inc.
1

376
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
Osadchii et al.
Scheme 1
Reagents and conditions: a. Concentrated HCl, MeOH, 60 °C. b. Br , CHCl , 25 °C. c. C H N, EtOH, 78 °C. d. C H N, CHCl ,
2
3
5
5
5
5
3
6
2
3 °C. e. Et N, CHCl , 63 °C. f. AcONa, AcOH, 118 °C. g. 10% KOH solution, 100 °C, and then H SO . h. Morpholine, CHCl ,
3
3
2
4
3
5 °C. i. MCPBA. j. NaOH, MeOH, 25 °C, and then H SO .
2
4
the bromine atom giving rise to 2ꢀ(1ꢀmethylethyl)ꢀ2ꢀ
morpholinoꢀ7Hꢀfuro[3,2ꢀg][1]benzopyranꢀ3,7ꢀdione (9)
in 72% yield.
Upon refluxing of compound 3 in glacial acetic acid in
the presence of anhydrous AcONa, the bromine atom
underwent nucleophilic substitution resulting in the
formation of 2ꢀacetoxyoreoselon, viz., 2ꢀacetoxyꢀ2ꢀ
ethyl)ꢀ7Hꢀfuro[3,2ꢀg][1]benzopyranꢀ3,7ꢀdione (8), in
83% yield.
Peucedanin (1) underwent an unexpected transforꢀ
mation upon oxidation with mꢀchloroperoxybenzoic acid
(MCPBA). The reaction of 1 with two equivalents of the
peroxy acid gave the known peuruthenicin isobutyrate
2
0
(12), which has been synthesized earlier and extracted
1
5
(
(
1ꢀmethylethyl)ꢀ7Hꢀfuro[3,2ꢀg][1]benzopyranꢀ3,7ꢀdione
7), in 27% yield. This reaction produced unsaturꢀ
from the plant. The possible reaction mechanism preꢀ
sented in Scheme 1 involves the following steps: 1) forꢀ
mation of intermediate peucedanin 2,3ꢀepoxide (10);
2) cleavage of the epoxy ring by the addition of the second
MCPBA molecule giving rise to peroxy ester 11; 3) subseꢀ
quent elimination of mꢀchlorobenzoic acid to form diꢀ
ated ketone 5 as the major product (the yield was 44%).
Dissolution of bromide 3 in a 10% KOH solution at high
temperature followed by neutralization of the solution
gave 2ꢀhydroxyoreoselon, viz., 2ꢀhydroxyꢀ2ꢀ(1ꢀmethylꢀ

Transformations of peucedanin
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
377
rectly compound 12. The mechanism of cleavage of bicyꢀ
clic tetrasubstituted olefins with MCPBA has been disꢀ
cussed earlier.21 It was demonstrated22 that 2ꢀmethylꢀ
added at a rate such that the temperature of the reaction mixture
was no higher than 60 °C. After cooling, the product was filtered
off and dried at 100 °C. The dry product was recrystallized from
refluxing 95% ethanol (620 mL). Oreoselon (2) was obtained in
4
,5,6,7ꢀtetrahydrobenzofuran undergoes analogous cleavꢀ
2
5
a yield of 24.2 g, m.p. 177—178 °C (cf. lit. data : m.p.
77—178 °C (from EtOH)). The mother liquor was concenꢀ
age with peroxy acids. An alternative mechanism involves
the transformation of peroxy ester 11 into 1,2ꢀdioxetane
derivative 14 followed by is decomposition to give isoꢀ
butyrate 12. In the plant, oxidation of peucedanin (1)
most likely starts with the addition of singlet oxygen givꢀ
ing rise to dioxetane 14 and completed with decomposiꢀ
tion of the latter to form compound 12. Data on the
synthesis of 1,2ꢀdioxetanes from enol ethers and their
1
trated to ~20 mL to give the second crop (1.7 g) of oreoselon.
1
The total yield was 25.9 g (90%). H NMR, δ: 0.81 and 1.10
(both d, 3 H each, Me C, J = 6.8 Hz); 2.31 (sept.d, 1 H,
2
H(1´), J = 6.8 Hz, J = 4.0 Hz); 4.48 (d, 1 H, H(2), J = 4.0 Hz);
6.27 (d, 1 H, H(6), J = 9.6 Hz); 6.93 (s, 1 H, H(9)); 7.67 (d, 1 H,
–
1
H(5), J = 9.6 Hz); 7.73 (s, 1 H, H(4)). IR, ν/cm : 496, 745,
14, 830, 936, 979, 1046, 1105, 1144, 1156, 1356, 1394, 1469,
1485, 1576, 1629, 1711, 1726 (C=O), 2931, 2964.
ꢀBromooreoselon (2ꢀbromoꢀ2ꢀ(1ꢀmethylethyl)ꢀ7Hꢀ
furo[3,2ꢀg][1]benzopyranꢀ3,7ꢀdione) (3). A solution of bromine
2.13 g, 13.3 mmol) in CHCl (13.3 mL) was added dropwise
8
2
3
decomposition were summarized in the publication. It
should be noted that, under the aboveꢀdescribed condiꢀ
tions, oreoselon (2) remains unconsumed.
2
(
3
Alkaline hydrolysis of isobutyrate 12 under mild conꢀ
ditions affords a compound (in 94% yield) identical to
natural peuruthenicin (13).1
To summarize, simple chemical transformations of
peucedanin provide a route to the synthesis of promising
coumarin derivatives.
with stirring to a solution of peucedanin (1) (3.44 g, 13.3 mmol)
in CHCl (26.6 mL), each drop of the bromine solution becomꢀ
3
5,20
ing colorless. After removal of the solvent in vacuo (the bath
temperature was 60 °C), the amorphous precipitate was dried at
1
0 Torr and triturated with diethyl ether (5 mL). Crystals of
compound 3 were filtered off. The yield was 3.97 g (92%), m.p.
1
8
1
3
1
40—141 °C (cf. lit. data : m.p. 140—141 °C). Found, m/z:
+
21.98409 [M] . C H BrO . Calculated: M = 321.98412.
H NMR, δ: 0.95 and 1.33 (both d, 3 H each, Me C, J = 6.8
1
4
11
4
Experimental
2
Hz); 2.51 (sept, 1 H, H(1´), J = 6.8 Hz); 6.37 (d, 1 H, H(6), J =
9.6 Hz); 7.01 (s, 1 H, H(9)); 7.73 (d, 1 H, H(5), J = 9.6 Hz);
The syntheses were performed with the use of freshly disꢀ
tilled solvents and reagents of highꢀpurity grade. The melting
points were determined on a Kofler apparatus. The IR spectra
were recorded on a Vector 22 spectrometer in KBr pellets. The
UV spectra were measured on a Specord UV—Vis spectrophoꢀ
tometer in ethanol (C = 10–4 mol L ). The molecular weights
and elemental compositions were determined on a highꢀresoluꢀ
tion Finnigan MAT 8200 mass spectrometer. The NMR spectra
were recorded on a Bruker AC 200 spectrometer (200.13 MHz
1
3
7.91 (s, 1 H, H(4)). C NMR, δ: 16.6 and 17.4 (both q,
(CH ) C); 36.4 (d, C(1´)); 98.9 (s, C(2)); 101.4 (d, C(9)); 115.2
3
2
(d, C(6)); 115.5 (s, C(3a)); 115.8 (s, C(4a)); 126.0 (d, C(4));
143.2 (d, C(5)); 158.7 (s, C(9a)); 161.1 (s, C(8a)); 169.4
–1
–1
(s, C(7)); 192.5 (s, C(3)). IR, ν/cm : 489, 724, 800, 837, 860,
918, 934, 1018, 1101, 1117, 1146, 1355, 1393, 1481, 1581, 1631,
1726, 1744 (C=O), 2980, 3081.
Reaction of 2ꢀbromooreoselon with pyridine. A. A mixture of
2ꢀbromooreoselon (3) (4.78 g, 14.8 mmol), dry pyridine (1.17 g,
14.8 mmol), and 95% ethanol (28 mL) was refluxed for 1.5 h.
After cooling, a precipitate of 2ꢀ(1ꢀmethylethylidene)ꢀ7Hꢀ
furo[3,2ꢀg][1]benzopyranꢀ3,7ꢀdione (5) was filtered off in a
1
13
for H and 50.32 MHz for C) for 10% solutions in CDCl3,
unless otherwise indicated, at 25 °C with resonance stabilization
based on the signal for the deuterium atom of the solvent. The
chemical shifts were measured relative to the signal of CHCl as
3
1
9
the internal standard (δ 7.24 and δC 76.90). The multiplicities
yield of 0.78 g (22%), m.p. 283—285 °C (cf. lit. data : m.p.
H
of the signals in the 13C NMR spectra were determined accordꢀ
ing to standard procedures using JMOD experiments and offꢀ
resonance proton irradiation. The assignment of the signals in
283—285 °C (from AcOH)). Found, m/z: 242.05822 [M] .
+
1
C H O . Calculated: M = 242.05790. H NMR (10% solution
14
10
4
in a CF CO D—CDCl mixture, 2 : 1, v/v, CHCl as the interꢀ
3
2
3
3
1
13
the H and C NMR spectra of compounds 3—9 was made
nal standard), δ: 2.30 and 2.48 (both s, 3 H each, Me C); 6.60
2
1
5
using the data for the model compound, viz., oreoselon.
(d, 1 H, H(6), J = 9.6 Hz); 7.29 (s, 1 H, H(9)); 8.07 (d, 1 H,
–
1
Peucedanin (1) was extracted from airꢀdry roots of
Peucedanum morisonii by refluxing in tertꢀbutylmethyl ether,
H(5), J = 9.6 Hz); 8.15 (s, 1 H, H(4)). IR, ν/cm : 513, 670,
751, 765, 845, 866, 1130, 1146, 1181, 1223, 1256, 1352, 1395,
1442, 1482, 1573, 1621, 1655, 1701, 1730 (C=O), 3047.
2
4
m.p. 85—87 °C (cf. lit. data : m.p. 85—87 °C (from Et O)).
2
1
H NMR, δ: 1.28 (d, 6 H, Me C, J = 6.8 Hz); 3.18 (sept, 1 H,
Ethanol was removed from the mother liquor in vacuo (the
bath temperature was 60—70 °C), and diethyl ether (10 mL) was
added to the cooled residue. The precipitate that formed was
thoroughly ground and filtered off. Nꢀ{2ꢀ(1ꢀMethylethyl)ꢀ3,7ꢀ
dioxoꢀ7Hꢀfuro[3,2ꢀg][1]benzopyranꢀ2ꢀyl}pyridinium bromide
monohydrate (4) was obtained as a powder in a yield of 4.15 g
(67%). Cooling of the hot solution in 95% ethanol afforded
colorless crystals of the product. After heating above 150 °C, the
latter was decomposed and turned yellowish. At a temperaꢀ
ture higher than 170 °C, colorless needleꢀlike crystals subꢀ
limed. Found (%): C, 54.45; H, 4.29; Br, 18.83; N, 3.10.
C H BrNO •H O (C H BrNO ). Calculated (%): C, 54.30;
2
H(1´), J = 6.8 Hz); 3.88 (s, 3 H, OMe); 6.28 (d, 1 H, H(6), J =
9
.6 Hz); 7.22 (s, 1 H, H(9)); 7.51 (s, 1 H, H(4)); 7.72 (d, 1 H,
1
5
–1
H(5), J = 9.6 Hz) (cf. lit. data ). IR, ν/cm : 823, 877, 1039,
1
1
120, 1142, 1214, 1284, 1364, 1390, 1444, 1461, 1577, 1634,
725 (C=O), 2933, 2972.
Oreoselon (2) was prepared by hydrolysis of peucedanin (1)
according to a known procedure.24 A mixture of peucedanin
(
30.4 g) and MeOH (152 mL) was heated to 55 °C on a water
bath until complete dissolution was achieved. Concentrated HCl
60 mL) was added dropwise with stirring to the hot solution, an
exothermic reaction being observed. Hydrochloric acid was
(
19
16
4
2
19 18
5

378
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
Osadchii et al.
1
H, 4.32; Br, 19.01; N, 3.33. H NMR (10% solution in CD OD),
identified by comparing its IR spectrum with the spectrum of
the authentic sample.
3
δ: 1.14 and 1.27 (both d, 3 H each, Me C, J = 6.8 Hz); 3.34
2
(
7
sept, 1 H, H(1″), J = 6.8 Hz); 6.62 (d, 1 H, H(6), J = 9.6 Hz);
.78 (s, 1 H, H(9)); 8.26 (d, 1 H, H(5), J = 9.6 Hz); 8.39 (s, 1 H,
2ꢀAcetoxyoreoselon (2ꢀacetoxyꢀ2ꢀ(1ꢀmethylethyl)ꢀ7Hꢀ
furo[3,2ꢀg][1]benzopyranꢀ3,7ꢀdione) (7). A mixture of 2ꢀbromoꢀ
oreoselon (3) (6.64 g, 20.6 mmol), anhydrous powdered AcONa
(3.46 g, 42.2 mmol), and glacial acetic acid (26 mL) was reꢀ
fluxed for 1 h. After cooling, the precipitate was filtered off,
washed with diethyl ether (3×10 mL), and dried. The residue
was thoroughly washed with water (3×10 mL) to remove an
impurity of sodium acetate and dried at 130 °C. Compound 5
was obtained in a yield of 2.20 g (44%), m.p. 283—285 °C. The
product was identified by comparing its IR spectrum with the
spectrum of the authentic sample. The acetic acid filtrate was
diluted with water (90 mL). The amorphous product that formed
was extracted with diethyl ether (4×20 mL), the extract was
washed with water (2×20 mL), the solvent was removed, and the
oily residue was triturated with diethyl ether (10 mL). The preꢀ
cipitate that formed was filtered off, recrystallized from AcOEt,
and dried. Compound 7 was obtained in a yield of 1.70 g (27%),
H(4)); 8.55 (br.t, 2 H, H(3´), H(5´), J = 7.5 Hz); 9.02 (tt, 1 H,
H(4´), J = 8.0 Hz, J = 1.0 Hz); 9.76 (br.d, 2 H, H(2´), H(6´),
J = 7.5 Hz). H NMR (5% solution in D O, H O as the internal
standard (δ 4.80)), δ: 0.88 and 1.01 (both d, 3 H each, Me C,
J = 6.8 Hz); 3.03 (sept, 1 H, Me CH, J = 6.8 Hz); 6.43 (d, 1 H,
1
2
2
2
2
H(6), J = 9.6 Hz); 7.48 (s, 1 H, H(9)); 7.99 (d, 1 H, H(5), J =
9
7
2
7
1
.6 Hz); 8.11 (s, 1 H, H(4)); 8.23 (br.t, 2 H, H(3´), H(5´), J =
.5 Hz); 8.70 (tt, 1 H, H(4´), J = 8.0 Hz, J = 1.0 Hz); 9.42 (br.d,
–
1
H, H(2´), H(6´), J = 7.5 Hz). IR, ν/cm : 512, 678, 700, 741,
55, 780, 827, 866, 937, 970, 1096, 1123, 1355, 1388, 1472,
529, 1583, 1628, 1745 (C=O), 2935, 2972, 3043. UV (EtOH),
λmax/nm (logε): 258 (4.46), 347 (3.97).
Storage of the oily residue, which was obtained after reꢀ
moval of diethyl ether from the ethereal filtrate, for one day
afforded crystals of 2ꢀethoxyoreoselon (2ꢀethoxyꢀ2ꢀ(1ꢀmethylꢀ
ethyl)ꢀ7Hꢀfuro[3,2ꢀg][1]benzopyranꢀ3,7ꢀdione) (6). The yield
was 0.30 g (7%), m.p. 124—125 °C (from diethyl ether). Found,
+
m.p. 140—141 °C. Found, m/z: 302.07928 [M] . C H O .
1
6
14
6
1
Calculated: M = 302.07903. H NMR, δ: 0.87 and 1.09 (both d,
+
m/z: 288.10002 [M] . C H O . Calculated: M = 288.09976.
1
3 H each, Me C, J = 6.8 Hz); 2.07 (s, 3 H, MeCO); 2.24 (sept,
16
16
5
2
H NMR, δ: 0.81 and 0.99 (both d, 3 H each, Me C, J =
1 H, H(1″), J = 6.8 Hz); 6.30 (d, 1 H, H(6), J = 9.6 Hz); 6.89 (s,
1 H, H(9)); 7.67 (d, 1 H, H(5), J = 9.6 Hz); 7.77 (s, 1 H, H(4)).
2
6
.8 Hz); 1.11 (t, 3 H, CH CH , J = 6.8 Hz); 2.17 (sept, 1 H,
3 2
13
H(1″), J = 6.8 Hz); 3.33 and 3.42 (both m, 1 H each, CH CH );
C NMR, δ: 15.0 and 15.1 (both q, (CH ) C); 19.9 (q, CH CO);
3
2
3 2 3
6
.28 (d, 1 H, H(6), J = 9.6 Hz); 6.90 (s, 1 H, H(9)); 7.67 (d, 1 H,
33.4 (d, C(1″)); 100.0 (d, C(9)); 105.5 (s, C(2)); 114.4 (s, C(3a));
114.4 (d, C(6)); 118.7 (s, C(4a)); 123.9 (d, C(4)); 143.3 (d, C(5));
13
H(5), J = 9.6 Hz); 7.74 (s, 1 H, H(4)). C NMR, δ: 14.9, 15.4,
and 15.7 (all q, Me); 34.1 (d, C(1″)); 60.5 (t, C(1´)); 100.3
159.1 (s, C(9a)); 160.7 (s, C(8a)); 168.3 (s, CH CO); 170.2
3
(s, C(7)); 194.2 (s, C(3)). IR, ν/cm– : 825, 889, 939, 962, 983,
1070, 1100, 1129, 1185, 1231, 1286, 1352, 1371, 1389, 1577,
1629, 1743 (C=O), 2940, 2969. UV, λmax/nm (logε): 214 (4.05),
222 (4.06), 254 (4.44), 296 (3.97), 306 (3.96), 348 (4.04).
2ꢀHydroxyoreoselon (2ꢀhydroxyꢀ2ꢀ(1ꢀmethylethyl)ꢀ7Hꢀ
furo[3,2ꢀg][1]benzopyranꢀ3,7ꢀdione) (8). A mixture of 2ꢀbromoꢀ
oreoselon (3) (516 mg, 1.60 mmol) and a 10% KOH solution
(4.50 g, 8.02 mmol) was refluxed with stirring for 15 min. The
resulting darkꢀcolored solution was cooled to 20 °C, and a 10%
H SO solution was added with stirring to pH 4. The oil that
1
(
1
(
d, C(9)); 112.4 (s, C(2)); 114.2 (s, C(3a)); 114.5 (d, C(6));
18.5 (s, C(4a)); 124.3 (d, C(4)); 143.3 (d, C(5)); 159.2
s, C(9a)); 161.5 (s, C(8a)); 172.1 (s, C(7)); 198.0 (s, C(3)). IR,
–
1
ν/cm : 828, 896, 913, 1001, 1040, 1190, 1290, 1350, 1394,
483, 1572, 1625, 1733 (C=O), 2977. UV, λmax/nm (logε): 223
1
(
4.26), 254 (4.54), 297 (4.16), 350 (4.23), 409 (3.50).
B. Dry pyridine (1.17 g, 14.8 mmol) was added to a solution
of 2ꢀbromooreoselon (3) (4.78 g, 14.8 mmol) in CHCl (28 mL).
3
The reaction solution was refluxed for 1.5 h, which was accomꢀ
panied by the formation of a solid residue. The mixture was
concentrated in vacuo (the bath temperature was 60 °C) to
2
4
formed was extracted with diethyl ether (3×5 mL). The ethereal
extract was filtered, and the solvent was removed. The residue
was dissolved in ethanol (4 mL) with heating. After cooling,
compound 8 was filtered off as yellowish needles. The yield was
345 mg (83%), m.p. 192—193 °C. Found (%): C, 64.30; H, 4.48.
~
10 mL. The precipitate was filtered off from the hot solution,
washed with hot CHCl3 (2×3 mL), and dried. The product
4.43 g) was triturated with hot (70 °C) water (2×44.3 mL).
The combined aqueous filtrates were concentrated in vacuo
(
1
(
(
the bath temperature was 60 °C) and the residue was dried
10 Torr). Monohydrate of salt 4 was obtained in a yield of
C H O . Calculated (%): C, 64.61; H, 4.65. H NMR (10%
14
12
5
solution in a CDCl —CD OD mixture, 3 : 1, v/v), δ: 0.74 and
3
3
3
.83 g (62%). The residue, which remained undissolved after
0.93 (both d, 3 H each, Me C, J = 6.8 Hz); 2.10 (sept, 1 H,
2
trituration with hot water, was dried on a filter at 10 Torr (the
bath temperature was 60 °C). Compound 5 was obtained in a
yield of 0.60 g (17%). Compounds 4 and 5 were identified by
comparing their IR spectra with the spectra of the authentic
samples.
H(1´), J = 6.8 Hz); 6.18 (d, 1 H, H(6), J = 9.6 Hz); 6.78 (s, 1 H,
H(9)); 7.64 (d, 1 H, H(5), J = 9.6); 7.68 (s, 1 H, H(4)).
13
C NMR, δ: 14.9 and 15.5 (both q, (CH ) C); 33.7 (d, C(1´));
3
2
100.2 (d, C(9)); 108.9 (s, C(2)); 113.7 (d, C(6)); 114.0 (s, C(3a));
117.5 (s, C(4a)); 124.8 (d, C(4)); 143.8 (d, C(5)); 159.8
(s, C(9a)); 161.2 (s, C(8a)); 171.7 (s, C(7)); 198.7 (s, C(3)). IR,
Reaction of 2ꢀbromooreoselon with triethylamine. 2ꢀBromoꢀ
oreoselon (3) (14.4 g, 44.6 mmol) was added with stirring to a
–
1
ν/cm : 453, 655, 743, 827, 858, 881, 920, 1012, 1196, 1327,
1355, 1394, 1471, 1482, 1570, 1627, 1711, 1732 (C=O), 2958,
3060, 3322 (OH). UV, λmax/nm (log ε): 223 (4.17), 253 (4.45),
299 (4.02), 350 (4.12), 410 (3.40).
solution of triethylamine (4.80 g, 47.5 mmol) in CHCl (84 mL).
3
The resulting solution was refluxed using a reflux condenser
equipped with a calcium chloride tube on a water bath for 1.5 h.
Water (30 mL) was added to the warm solution and the mixture
was vigorously stirred. The precipitate that formed was filtered
off and washed with a minimum amount of chloroform and
water and then dried in a drying oven at 130 °C. Compound 5
was obtained in a yield of 5.06 g (47%), m.p. 283—285 °C, and
2ꢀ(1ꢀMethylethyl)ꢀ2ꢀmorpholinoꢀ7Hꢀfuro[3,2ꢀg][1]benzoꢀ
pyranꢀ3,7ꢀdione (9). 2ꢀBromooreoselon (3) (998 mg, 3.09 mmol)
was added with stirring to a solution of morpholine (552 mg,
6.34 mmol) in CHCl (5.8 mL). The resulting solution was kept
3
at 25 °C for 24 h. Then the reaction mixture containing the

Transformations of peucedanin
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 2, February, 2006
379
precipitate that formed was mixed with water (4 mL). The aqueꢀ
ous layer was separated. The organic layer was washed with water
2. R. D. H. Murray, The Naturally Occurring Coumarins.
Progress in the Chemistry of Organic Natural Products,
SpringerꢀVerlag, Wien, 2002, 83, 673 pp.
(2×4 mL) to remove traces of waterꢀsoluble products. Chloroꢀ
form was evaporated in vacuo. The residue was triturated with
diethyl ether (3×4 mL), dried, and recrystallized from refluxing
anhydrous ethanol (28 mL). Compound 9 was obtained as yelꢀ
lowish needles in a yield of 733 mg (72%), m.p. 200 °C (decomp.).
3. I. V. Nagorichna, I. P. Dubovik, M. M. Garazd, and V. P.
Khilya, Khim. Prirod. Soedin., 2003, 196 [Chem. Nat. Compd.,
2003 (Engl. Transl.)].
4. M. D. Mashkovskii, Lekarstvennye sredstva [Drugs], 14th ed.,
Novaya Volna, Moscow, 2001, 2, 223 (in Russian).
5. H. Yuan and A. L. Parrill, Bioorg. Med. Chem., 2002, 10, 4169.
6. P. C.ꢀM. Mao, J.ꢀF. Mouscadet, H. Leh, C. Auclair, and
L.ꢀY. Hsu, Chem. Pharm. Bull., 2002, 50, 1634.
7. Y. Kashman, K. R. Gustafson, R. W. Fuller, J. H. Cardellina,
J. B. McMahon, M. J. Currens, R. W. Buckheit, Jr., S. H.
Hughes, G. M. Crag, and M. R. Boid, J. Med. Chem., 1992,
35, 2735.
8. L. Huang, Y. Kashiwada, L. M. Cosentino, Sh. Fan, Ch.ꢀH.
Chen, A. T. McPhail, T. Fujioka, K. Mihashi, and K.ꢀH.
Lee, J. Med. Chem., 1994, 37, 3947.
9. C. Ito, M. Itoigawa, H. Furukawa, H. Tokuda, Y. Okuda,
T. Mukainaka, M. Okuda, and H. Nishino, Cancer Lett.,
1999, 138, 87.
+
Found, m/z: 329.12559 [M] . C18H19NO5. Calculated:
1
M = 329.12631. H NMR, δ: 0.66 and 1.04 (both d, 3 H each,
Me C, J = 6.8 Hz); 2.38—2.78 (m, 5 H, C(2´)H , C(6´)H ,
2
2
2
H(1″)); 3.48—3.69 (m, 4 H, C(3´)H , C(5´)H ); 6.22 (d, 1 H,
2
2
H(6), J = 9.6 Hz); 6.82 (s, 1 H, H(9)); 7.64 (d, 1 H, H(5), J =
.6 Hz); 7.68 (s, 1 H, H(4)). 13C NMR, δ: 14.8 and 16.2 (both q,
Me); 30.9 (d, C(1″)); 46.0 (t, C(2´), C(6´)); 66.3 (t, C(3´), C(5´));
9
9
1
1
5
1
9.7 (d, C(9)); 109.1 (s, C(2)); 113.7 (s, C(3a)); 114.0 (d, C(6));
19.5 (s, C(4a)); 124.0 (d, C(4)); 143.3 (d, C(5)); 159.1 (s, C(9a));
–1
61.4 (s, C(8a)); 172.4 (s, C(7)); 197.3 (s, C(3)). IR, ν/cm
:
18, 826, 848, 878, 904, 1091, 1121, 1144, 1191, 1288, 1347,
392, 1484, 1624, 1720, 1747 (C=O), 2855, 2970. UV, λmax/nm
(
logε): 224 (4.16), 254 (4.44), 299 (4.12), 350 (4.23), 353 (4.06).
Oxidation of peucedanin (1) with mꢀchloroperoxybenzoic acid.
A solution of MCPBA (1.94 g, 11.2 mmol) in CHCl (11.3 mL)
was added dropwise to a solution of peucedanin (1) (1.40 g,
10. C. Ito, M. Itoigawa, Y. Mishina, V. C. Filho, F. Enjo,
H. Tokuda, H. Hishino, and H. Furukawa, J. Nat. Prod.,
2003, 66, 368.
3
5
.43 mmol) in CHCl (5.4 mL), the mixture being cooled with
3
running water to 20—25 °C. The reaction mixture was kept for
6 h. Then a saturated NaHCO solution (10 mL) was carefully
11. D. Guilet, J.ꢀJ. Helesbeux, D. Seraphin, T. Sevenet,
P. Richomme, and J. Bruneton, J. Nat. Prod., 2001, 64, 563.
12. G. Appendino, F. Bianchi, A. Bader, C. Campagnuolo,
E. Fattorusso, O. TaglialatelaꢀScafati, M. BlancoꢀMolina,
A. Macho, and B. L. Fiebich, J. Nat. Prod., 2004, 67, 532.
13. Flora Sibiri [Siberian Flora], Eds L. I. Malyshev and G. A.
Peshkova, Nauka, Novosibirsk, 1996, 10 (in Russian).
14. V. B. Kuvaev, Rastitel´nye resursy [Plant Resources], 1966, 2,
223 (in Russian).
15. E. E. Shults, T. N. Petrova, M. M. Shakirov, E. I. Chernyak,
L. M. Pokrovskii, S. A. Nekhoroshev, and G. A. Tolstikov,
Khimiya v interesakh ustoichivogo razvitiya, 2003, 11, 683
[Chemistry for Sustainable Development, 2003, 11 (Engl.
Transl.)].
1
3
added (foaming can occur!) with stirring to the mixture containꢀ
ing the precipitate of 3ꢀchlorobenzoic acid that formed. The
organic layer was separated and twice treated with a NaHCO3
solution (the last portion of the washing bicarbonate solution
did not give a precipitate of 3ꢀchlorobenzoic acid upon acidifiꢀ
cation with 10% H SO ). After storage, the transparent organic
2
4
solution was decanted, the solvent was removed, and the solid
residue was recrystallized from MeOH. Peuruthenicin isoꢀ
butyrate (12) was obtained as colorless crystals in a yield of
2
0
0
.90 g (57%), m.p. 133—134 °C (cf. lit. data : m.p. 133—134 °C
(
MeOH)). The product was identified by comparing its mass
1
13
spectrum, H and C NMR spectra, and IR spectrum with the
data published in the literature.1
5
16. A. I. Nagiev, I. S. Mamedov, S. Wunderlich, G. A.
Kuznetsova, L. I. Shagova, and A. Ya. Potapenko, J. Chem.
Biochem. Kinet., 1992, 2, 3.
Alkaline hydrolysis of peuruthenicin isobutyrate (12). Comꢀ
pound 12 (63 mg, 0.22 mmol) was added to a solution of NaOH
(
103 mg, 2.58 mmol) in a solution of equal volumes (0.9 mL
17. E. M. Vermel´ and S. A. KruglyakꢀSyrkina, Voprosy onkologii
[Problems of Oncology], 1959, 5, 43 (in Russian).
18. A. Jassoy and P. Haensel, Arch. Pharm. Ber. Deutsch. Pharm.
Ges., 1898, 236, 662.
19. F. Bruchhausen and H. Hoffmann, Ber. Deutsch. Chem. Ges.,
1941, 74B, 1584.
20. V. K. Ahluwalia and C. Prakash, Indian J. Chem., 1977,
15B, 423.
21. I. J. Borowitz, G. J. Williams, L. Gross, and R. Rapp, J. Org.
Chem., 1968, 33, 2013.
each) of water and MeOH. After stirring for 2 h, the resulting
yellowish solution was acidified with 10% H SO to pH 4. The
precipitate that formed was dried in air and dissolved in CHCl3.
The solution was filtered off and concentrated to dryness.
Peuruthenicin 13 was obtained in a yield of 45 mg (94%), m.p.
2
4
2
0
1
95—197 °C (cf. lit. data : m.p. 195—197 °C (from a benꢀ
zene—petroleum ether mixture)). The product was identified by
comparing its H NMR spectrum with the data published in the
literature.15
1
2
2. S. B. Ginserich and P. W. Jennings, J. Org. Chem., 1983,
8, 2606.
3. G. L. Sharipov, V. P. Kazakov, and G. A. Tolstikov, Khimiya
i khemilyuminestsentsiya 1,2ꢀdioksetanov [Chemistry and
Chemoluminescence of 1,2ꢀDioxetanes], Nauka, Moscow,
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 03ꢀ03ꢀ33093)
and the Siberian and FarꢀEastern Branches of the Rusꢀ
sian Academy of Sciences (Integration Project No. 43).
4
2
1
990, 288 pp. (in Russian).
2
2
4. H. Schmid and A. Ebnoether, Helv. Chim. Acta, 1951, 34, 1982.
5. E. Spaeth, H. Klager, and O. Schlosser, Ber., 1931, 64B, 2203.
References
1
. R. D. H. Murray, J. Mendez, and S. A. Brown, The Natural
Coumarins, J. Wiley, Chichester, 1982, 702 pp.
Received November 12, 2004;
in revised form November 17, 2005